Recent understanding of clinical sequencing and gene-based risk stratification in inherited primary arrhythmia...

Inherited primary arrhythmia syndromes (IPAS) may result in ventricular tachycardia or ventricular fibrillation by some genetic disorders, leading to sudden cardiac death. IPAS are also called "channelopathies" since many of these are caused by an abnormality in myocardial ion channels. Congenital long-QT syndrome (LQTS) is the most well documented IPAS, which may be seen in 0.1% of the general population. More than 15 disease-causing genes have been identified in almost 70% of LQTS patients and genetic testing is well applied to not only clinical diagnosis but also risk stratification and gene-based therapeutic strategy for each person with LQTS. Thus, in LQTS, gene-based personalized medicine can be realized. Unlike the LQTS, genetic testing for the Brugada syndrome (BrS) is still controversial since only 20% of patients can be identified with the causing gene mutations, most of which are in SCN5A. Furthermore, even in the SCN5A mutation-positive carriers, their phenotypes are not completely consistent with BrS, but may cause other IPAS including LQTS, cardiac conduction defect, sick sinus syndrome, and dilated cardiomyopathy. On the other hand, a recent Japanese BrS registry demonstrated that the pore-region mutations in SCN5A are significantly associated with a risk of lethal cardiac events. Furthermore, a genome-wide association study revealed that a common variant in SCN10A or HEY2 in addition to SCN5A is associated with BrS, thus, BrS may not be a monogenic Mendelian disease but probably an oligogenic disease. The purpose of this review is to describe the basic genetic and pathophysiological findings of the IPAS, particularly LQTS and Brugada syndrome, and to outline a rational approach to genetic testing, management, and family screening.